Objective 1: Decipher dynamic cell shape changes and tissue fluidization in epidermal stratification
In this objective, a new mechanism of how coordination of compressive and contractile forces drives cell shape and fate changes to generate the epidermal hair follicle placode was discovered. Specifically, the researcher identified a key role for coordinated mechanical forces stemming from contractile, proliferative, and proteolytic activities across the epithelial and mesenchymal compartments in generating the placode structure. A ring of fibroblast cells gradually wraps around the placode cells to generate centripetal contractile forces, which in collaboration with polarized epithelial myosin activity promote elongation and local tissue thickening. Subsequently, proteolytic remodeling locally softens the basement membrane to facilitate release of pressure on the placode, enabling localized cell divisions, tissue fluidification, and epithelial invagination into the underlying mesenchyme. Together, the experimental data and modeling identify dynamic cell shape transformations and tissue-scale mechanical co-operation as key factors for orchestrating organ formation. This work is published as a preprint (
https://www.biorxiv.org/content/10.1101/2022.12.12.519937v1(se abrirá en una nueva ventana)) has been presented as poster and oral presentation at a number of conferences, and is currently under revision in a peer-reviewed journal.
Objective 2: Unravelling molecular mechanism of force-mediated regulation of stem cell fate
Here, the researcher has addressed the mechanism by which the epidermal stem cells commit to differentiation to form the life-essential skin barrier. Using single-cell RNA sequencing, the researcher discovered a committed stem cell population in the basal compartment that emerges during development, when tissue compartmentalization in the epidermis is being established. The emergence of the committed cell that will eventually delaminate coincides with profound changes in tissue packing and maturation of the extracellular matrix and adhesion. Additional analyses have indicated a signaling mechanism that triggers the differentiation of the stem cells. Remaining work aims at investigating how the mechanical properties of the tissue and cells coordinate this signaling activity to drive cell fate commitment. Understanding this connection will generate fundamental knowledge on how tissue growth and differentiation are coordinated. The work is expected to be complete end of 2023, after which it will be published as a preprint and submitted to a peer-reviewed journal.
